A Phase 2 Trial of Ivonescimab for Patients With Advanced, Metastatic Salivary Gland Cancers

Inclusion Criteria:

• Participants must have histologically confirmed salivary gland carcinoma (anyhistologic subtype, including ACC) with evidence of recurrent, metastatic, oradvanced, unresectable disease.

• Willing to provide tumor tissue from a diagnostic biopsy or prior surgery if deemedsafe and feasible by the investigator.

• Age 18 years or older at the time of consent. There is no upper age limitrestriction in an effort to include patients across the lifespan.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

• Participant must have organ and marrow function as defined below within 14 daysprior to study registration:

• Absolute neutrophil count (ANC) ≥1000/mcL

• Hemoglobin ≥8.5 g/dL (with no blood transfusions within 7 days of start oftherapy)

• Platelets ≥100,000/mcL

• Liver function:

• Serum total bilirubin (T-bili) ≤1.5× upper limit of normal (ULN); forpatients with liver metastases or confirmed/suspected Gilbert syndrome,T-bili ≤3× ULN

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×ULN; for patients with liver metastases, AST and ALT ≤5× ULN

• Creatinine Within normal limits, or Creatinine clearance (CrCl) ≥50 mL/minusing the Cockcroft-Gault formula or estimated glomerular filtration rate (eGFR) value ≥50 mL/min using the Chronic Kidney Disease EpidemiologyCollaboration (CKD-EPI) equation (adjustment by BSA is not required for eGFR)

• Urine protein: Urine protein <2+ or 24-hour urine protein quantification <1.0 g

• Coagulation:prothrombin time (PT) or international normalized ratio (INR) ≤1.5×ULN, and partial prothrombin time (PTT) or activated partial thromboplastintime (aPTT) ≤1.5× ULN (unless abnormalities are unrelated to coagulopathy orcoagulation)

• Participants must have documentation of a new or progressive lesion on a radiologicimaging study performed within 12 months prior to study registration (progression ofdisease over any interval is allowed) and/or new or worsening disease-relatedsymptoms within 12 months prior to study registration. This assessment is performedby the treating investigator. Evidence of progression by RECIST v1.1 criteria is notrequired.

• Participants must have at least one RECIST v1.1 measurable non-CNS based lesion, asdefined as at least one lesion that can be accurately measured in at least onedimension (longest diameter to be recorded for non-nodal lesions and short axis fornodal lesions) ≥1 cm with CT scans or MR imaging.

• Prior systemic therapy: At least 2 weeks must have elapsed since the end of priorchemotherapy, biological agents (3 weeks for anti-cancer monoclonal antibodycontaining regimens) or any investigational drug product, with adequate recovery oftreatment-related toxicity to NCI CTCAE Version 5.0 grade ≤1 (or tolerable grade 2)or back to baseline (except for alopecia or neuropathy). Any number of priortherapies for recurrent/metastatic SGC are permitted except receipt of a prior oralVEGFR TKI or anti-PD-1 therapy; but prior therapy for recurrent/metastatic SGC isnot required for participation.

• Ability to understand and the willingness to sign a written informed consentdocument.

• Female subjects of childbearing potential should have a negative urine or serumpregnancy test within 14 days of study registration. Female subjects of childbearingpotential should have a negative urine or serum pregnancy test repeated within 72hours prior to receiving the first dose of study medication.

• Female patient of childbearing potential having sex with an unsterilized malepartner must agree to use a highly effective method of contraception from thebeginning of screening until 120 days after the last dose of the Ivonescimab.

• Unsterilized male patient having sex with a female partner of childbearing potentialmust agree to use an effective method of contraception from the beginning ofscreening until Day 120 after the last dose of Ivonescimab.

Exclusion Criteria:

• Participant has known active central nervous system (CNS) metastases and/orcarcinomatous meningitis. Subjects with previously treated brain metastases mayparticipate provided they are stable (without evidence of progression by imaging forat least four weeks prior to the first dose of trial treatment) and have no evidenceof new or enlarging brain metastases.

• Concurrent administration of other cancer specific therapy or investigational agentsduring the course of this study is not allowed.

• Uncontrolled intercurrent illness including but not limited to ongoing or activeinfection, symptomatic congestive heart failure, unstable angina pectoris, orcardiac arrhythmia.

• Pregnant or lactating women as the effects of the investigational therapy (ivonescimab) on the developing human fetus are unknown.

• Has a known additional malignancy that is progressing or requires active treatment.Exceptions include basal cell carcinoma of the skin or squamous cell carcinoma ofthe skin that has undergone potentially curative therapy or in situ cervical cancer,and low- risk prostate adenocarcinoma being managed with active surveillance. Ahistory of another separate malignancy in remission without evidence of activedisease in the last 2 years is permitted.

• Existing significant autoimmune conditions. Patients with a history of Hashimotothyroiditis who are stable on replacement hormone therapy are not excluded. Patientscannot be on long-term (>4 weeks) corticosteroids at doses exceeding prednisone 10mg daily (or its equivalent).

• Major surgical procedures or serious trauma within 4 weeks prior to starting therapyor plans for major surgical procedures within 4 weeks after the first dose (asdetermined by the investigator). Minor local procedures (excluding central venouscatheterization and port implantation) are permitted.

• History of bleeding tendencies or coagulopathy and/or clinically significantbleeding symptoms or risk within 4 weeks prior to the start of therapy, includingbut not limited to:

• a. Gastrointestinal bleeding

• b. Hemoptysis (defined as coughing up ≥0.5 teaspoon of fresh blood or smallblood clots). Note: transient hemoptysis associated with diagnosticbronchoscopy is allowed.

• c. Significant nasal bleeding/epistaxis (bloody nasal discharge is allowed)

• d. Need for therapeutic anticoagulant therapy within 14 days prior to the startof therapy.

• Current hypertension with systolic blood pressure ≥150 mmHg or diastolic bloodpressure ≥100 mmHg after oral antihypertensive therapy.

• History of major diseases , specifically:

• a. Unstable angina, myocardial infarction, congestive heart failure (New YorkHeart Association [NYHA] classification ≥ grade 2) or vascular disease (eg,aortic aneurysm at risk of rupture) that required hospitalization within 12months prior to randomization, or other cardiac impairment that may affect thesafety evaluation of the study drug (eg, poorly controlled arrhythmias,myocardial ischemia)

• b. History of esophageal gastric varices, severe ulcers, wounds that do notheal, abdominal fistula, intra-abdominal abscesses, or acute gastrointestinalbleeding within 6 months before randomization

• c. History of arterial thromboembolic event, venous thromboembolic event ofGrade 3 and above as specified in National Cancer Institute (NCI) CommonTerminology Criteria for Adverse Events (CTCAE) 5.0, transient ischemic attack,cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathywithin 6 months prior to randomization

• d. Acute exacerbation of chronic obstructive pulmonary disease within 4 weeksbefore randomization

• e. History of perforation of the gastrointestinal tract and/or fistula, historyof gastrointestinal obstruction (including incomplete intestinal obstructionrequiring parenteral nutrition), extensive bowel resection (partial colectomyor extensive small bowel resection) within 6 months prior to randomization

• Imaging during the screening period shows that the patient has:

• a. Radiologically documented evidence of major blood vessel invasion orencasement by cancer (per the judgment of the treatment investigator)

• b. Radiographic evidence of intratumor cavitation (per the judgment of thetreating investigator)